COVID-19 Treatment Options

A further two medicines have received provisional registration from the Therapeutic Goods Administration (TGA) for the treatment of coronavirus disease 2019 (COVID-19. The following seven medicines are now provisionally approved, with a further agent under evaluation.

Remdesivir

On 10 July 2020, remdesivir became the first COVID-19 treatment to be provisionally approved by the TGA. Remdesivir is indicated for the treatment of COVID-19 in patients 12 years of age and older (weighing at least 40kg) with pneumonia who require supplemental oxygen.

The ACTT-1 trial was conducted in patients hospitalised with COVID-19 who had evidence of lower respiratory tract infection. It provided efficacy data for remdesivir courses of up to ten days. Patients randomised to the remdesivir group had a median recovery time of ten days, compared to 15 days for the placebo group. The estimated mortality was 6.7% in the remdesivir group and 11.9% for placebo at day 15 (11.4% and 15.2% at day 29, respectively).

Remdesivir is administered daily as an intravenous infusion for five to ten days. It is recommended to test renal and liver function prior to initiating therapy and during treatment, as appropriate. During clinical trials, transaminase elevations have been observed in both healthy volunteers and patients with COVID-19. Severe renal toxicity has also been observed during animal studies of remdesivir, although the significance for humans is unknown. Remdesivir is not recommended for patients with an eGFR < 30mL/minute.

Sotrovimab

Sotrovimab was granted provisional approval in August 2021. This monoclonal antibody is indicated for the treatment of COVID-19 in patients 12 years of age and older (weighing at least 40kg) who are at increased risk of disease progression but do not require initiation of oxygen. It is not indicated for patients hospitalised due to COVID-19.

Sotrovimab binds to a highly conserved epitope on the spike protein receptor-binding domain of SARS-CoV-2, the virus that causes COVID-19. This blocks a step prior to viral and cell membrane fusion, which results in reduced viral replication.

The COMET-ICE trial investigated the efficacy of sotrovimab, the primary efficacy outcome being hospitalisation for more than 24 hours or death within 29 days after randomisation. Sotrovimab resulted in an 85% relative risk reduction for this primary outcome. In addition, no patients in the sotrovimab group were admitted to the intensive care unit compared to five in the placebo group.

Sotrovimab is administered as a single intravenous infusion that should be given within five days of symptom onset. No dosage adjustments are required in renal impairment, hepatic impairment, or the elderly.

Casirivimab + imdevimab

Casirivimab + imdevimab gained provisional approval in October 2021. These monoclonal antibodies are indicated for the treatment of COVID-19 in patients 12 years of age and older (weighing at least 40kg) who do not require supplemental oxygen but are at higher risk of progressing to severe disease. It is also indicated for post-exposure prophylaxis in patients who are not vaccinated against COVID-19 or have a medical condition that makes them unlikely to be adequately protected by vaccination. However, it is not intended to be a substitute for vaccination.

Casirivimab and imdevimab are supplied in separate vials that can be administered intravenously or subcutaneously. Both agents are administered together as a single infusion when given intravenously. When administered subcutaneously, the two medicines are given consecutively by separate injections. Intravenous use is highly recommended, with subcutaneous administration an alternative when an intravenous infusion is not appropriate or would lead to treatment delays.

These two antibodies block the spike protein receptor-binding domain of the virus, thereby preventing the virus from infecting healthy cells. For treatment, it should be initiated as soon as possible after a positive COVID-19 test and not later than seven days after symptom onset. For prophylaxis, it should be initiated as soon as possible after exposure to SARS-CoV-2.

The efficacy of this medicine for the treatment of COVID-19 was evaluated in the COV-2067 trial. The primary endpoint (hospitalisation or death) had a relative risk reduction of around 70% in the active group compared to placebo. For the prevention of COVID-19, the COV-2069 trial demonstrated an 81% risk reduction in the development of symptomatic COVID-19.

Tocilizumab

In December 2021, tocilizumab was granted provisional approval for the treatment of COVID-19 in hospitalised adults. Patients must be receiving systemic corticosteroids and require supplemental oxygen or mechanical ventilation.

In contrast to other agents approved for COVID-19, tocilizumab is not specific for the SARS-CoV-2 virus. Tocilizumab is a monoclonal antibody that blocks the interleukin-6 receptor. Interleukin-6 is thought to play a key pathogenic role in SARS-CoV-2-induced cytokine storm, an aggressive inflammatory response associated with very poor outcomes.

Studies demonstrate that tocilizumab reduces the duration of hospitalisation, risk of requiring mechanical ventilation, and risk of death for patients with severe COVID-19. Tocilizumab is available in both intravenous and subcutaneous presentations. Only the intravenous formulation is approved for the treatment of COVID-19.

Regdanvimab

Regdanvimab was also granted provisional approval in December 2021. It is indicated for the treatment of adults with COVID-19 who do not require supplemental oxygen but are at increased risk of progressing to severe disease.

This monoclonal antibody binds to the receptor-binding domain of the spike protein, thereby blocking its entry into cells. In a randomised, double-blind clinical trial, the proportion of patients with worsening disease (requiring hospitalisation, oxygen therapy, or resulting in death) was 3.1% in the regdanvimab group compared to 11.1% in the placebo group (72.3% relative risk reduction).

Regdanvimab is administered as a single intravenous infusion which should be given within seven days of symptom onset.

Nirmatrelvir + ritonavir

Nirmatrelvir + ritonavir was granted provisional approval in January 2022. It is indicated for the treatment of COVID-19 in patients 18 years of age and older who do not require supplemental oxygen but are at increased risk of progression to hospitalisation or death. While this product is not recommended to be initiated in patients requiring hospitalisation due to COVID-19, the full five-day course may be completed if the patient goes on to require hospitalisation.

Nirmatrelvir inhibits the SARS-CoV-2 main protease, an enzyme required for viral replication. Ritonavir is used to increase the plasma levels of nirmatrelvir by inhibiting its hepatic metabolism. The two agents are supplied as separate tablets that must be taken together.

The primary efficacy endpoint of the EPIC-HR trial was COVID-related hospitalisation or death. The nirmatrelvir + ritonavir group showed an absolute reduction of 5.81% for this endpoint and a relative reduction of 88.9% compared to placebo. No deaths were reported in the active drug group, compared to nine deaths in the placebo group.

This medication inhibits CYY3A. It is contraindicated with medicines highly dependent upon this pathway for clearance and for which elevated plasma concentrations may result in serious adverse effects (e.g. alfuzosin, amiodarone, flecainide, colchicine, simvastatin, and diazepam). Use is also contraindicated with potent CYP3A inducers due to a potential loss of virologic response and development of resistance. This includes apalutamide, carbamazepine, phenobarbital, phenytoin, rifampicin, and St John’s Wort. The product information contains a complete list of established and potentially significant drug interactions.

Molnupiravir

Molnupiravir is the latest treatment for COVID-19, gaining provisional approval on 18 January 2022. It is indicated for the treatment of COVID-19 in adults who do not require initiation of oxygen and who are at increased risk of hospitalisation or death.

Following metabolism to its active form, molnupiravir is incorporated into viral RNA to inhibit viral replication. This oral treatment is recommended to be given twice daily for five days. It should be initiated as soon as possible after diagnosis and within five days of symptom onset. Early trial results suggested that molnupiravir reduced the risk of hospitalisation by 50%. However, more recent data has produced an adjusted relative risk reduction of 30%.

The potential for molnupiravir to interact with concomitant medications is considered unlikely as it is not an inducer, inhibitor, or substrate of major drug metabolising enzymes or transporters.

Summary

A summary of the provisionally approved therapies is shown in Table 1. The National COVID-19 Clinical Evidence Taskforce provides clinical flowcharts on how these agents may fit into therapy for various populations.

Table 1. Summary of provisionally approved COVID-19 treatments

*Repeat doses for ongoing prophylaxis may be considered

It is worth noting that the provisional approval of these agents for the treatment and prophylaxis of COVID-19 is based on preliminary clinical data. The TGA continues to monitor the safety of these agents, and healthcare professionals are encouraged to report any suspected adverse effects.